DESCRIPTION (Applicant's Abstract): Venereal syphilis is a chronic inflammatory disorder driven by the persistence of its etiologic agent Treponema pallidum. Research in this proposal is based on the premise that the local (i.e., tissue-based) cellular immune responses to T. pallidum have two distinct, yet interrelated, consequences of fundamental importance to syphilis pathogenesis. They cause the tissue damage which ultimately gives rise to clinical manifestations, and they are primarily responsible for the clearance of bacteria, a prerequisite for lesion resolution. Human skin is the primary focus of our efforts to elucidate these processes because (a) it is the major target organ of early syphilitic infection, (b) it is easily accessible to in vivo experimentation, and (c) there exists a wealth of reagents and information concerning its immune-related functions. During the prior funding interval, we have made considerable progress in characterizing the cellular infiltrates in secondary syphilis lesions and in delineating the ontogeny of the cutaneous response engendered by the syphilis spirochete. A unifying theme of this work has been the acquisition of considerable evidence, using a combination of in vitro and in vivo approaches, to support our primary hypothesis that the proinflammatory properties of treponemal lipoproteins are the primary triggers of innate immune mechanisms in early syphilis. More recently, we have shown that by recruiting a cellular infiltrate rich in antigen presenting cells, particularly dendritic cells, and memory/effector T cells, the innate immune processes induced by these lipid-modified polypeptides set the stage for the adaptive (i.e., specific) immune responses to the bacterium. One important outcome of these findings is the recognition that the cutaneous responses under investigation relate to primary as well as to secondary syphilis. In this competitive renewal application, we will extend this conceptual framework by further characterizing the in vivo biological responses to treponemal lipoproteins/lipopeptides (Aim One); by further characterizing the cutaneous immune response to T pallidum in secondary syphilis lesions (Aim Two); by using in vitro/ex vivo approaches to examine dendritic and T cell responses to T pallidum and treponemal proteins (Aim Three); and by examining our hypothesis that treponemal lipoproteins activate macrophages following uptake and degradation within the phagosomal vacuoles of macrophages (Aim Four). This work will result in an enhanced appreciation of the role of local cellular responses in syphilis pathogenesis and will provide a necessary underpinning for the eventual development of a safe and effective syphilis vaccine.